Chronic Obstructive Pulmonary Disease (COPD) is a disabling disorder that affects millions of people and is a leading cause of death in the U.S. and worldwide. Although smoking cessation can halt progression of early disease, once the disease becomes advanced, it may progress even with smoking cessation. Recent evidence suggests that progression of COPD is the result of dysregulation of cellular maintenance processes in the lung that result in apoptosis leading to emphysema. The complex interplay of oxidative stress, inflammatory cytokines, growth factors, and proteases promote this process leading to parenchymal destruction and airway remodeling. The thematic underpinning of this SCCOR is that understanding the processes leading to structural progression of COPD will lead to treatments that can halt clinical progression of the disease. The projects in this SCCOR explore key pathways that are involved in progression of COPD - novel anti-apoptotic properties of anti-proteases, genetic susceptibility to oxidative stress, the pro-inflammatory effects of particulate inhalation, and the pro-inflammatory stress of intermittent hypoxia. Innovative clinical therapeutic trials investigate anti-inflammatory agents and growth factor inhibitors, environmental controls, and mechanical support of nocturnal ventilation - all of which are promising treatments to stop progression of COPD. Highly focused basic proteomic research addresses the post-translational modification of alpha-1 anti-trypsin and highly focused genomic research addresses the role of the anti-oxidant regulatory gene Nrf2. The Hopkins SCCOR application represents a consortium of investigators with multidisciplinary expertise, and the common goal to translate basic research discoveries into direct benefit for patients with COPD. Supported by four interactive cores (Administration, Imaging, Patient Recruitment and Data Management, and Molecular Pathophysiology), the five human and animal projects will use state-of-the-art molecular approaches and novel phenotyping methods that will not only provide the deepest understanding of critical pathobiologic processes in COPD to date, but will define key pathways relevant to disease susceptibility and uncover new therapeutic approaches to modify the course of this disease.